High Polar Surface Area Research Articles

In Silico Molecular Docking of Phytochemicals of Murraya koenigii Against Streptococcus mutans.

Background The curry leaf tree, Murraya koenigii, is a tropical to subtropical tree in the family Rutaceae that is native to Asia. The plant parts are shown to have potential antimicrobial, antioxidant, antifungal, antidiarrheal, antidiabetic, anticancer, and anti-inflammatory properties. Streptococcus mutans is a facultative anaerobic, Gram-positive cocci, a common inhabitant of the human oral cavity that forms biofilms, contributing to dental caries. Aim The study aimed to analyze the inhibitory potential of phytocompounds in M. koenigii against the oral pathogen S. mutans. Materials and methods The protein and ligand were prepared, and molecular docking was carried out using the Hex protein docking server. The PyMOL program was used to view, analyze, and annotate the docked complex. The interaction of the drug, including the mechanism of action, and predicted adverse effects were predicted using the Way2Drug PASS Online server. The absorption, distribution, metabolism, excretion, and toxicity properties of the drug candidates were analyzed using the SwissADME online server. Results The study identified O-methyl murrayamine, koenigine, koenigicine, and murrayone as having inhibitory potential against the glycosyltransferase protein of S. mutans. Among the four compounds analyzed for docking, koenigicine had the lowest E-score, indicating a strong interaction with the receptor. Among the four compounds analyzed, murrayone had a high topological polar surface area score, while all four compounds had similar bioavailability scores. Conclusion This study concluded that O-methyl murrayamine, koenigine, koenigicine, and murrayone exhibit potent inhibitory potential against S. mutans. M. koenigiileaf extract can be used in toothpaste as an antibacterial agent to protect teeth against dental caries. These findings are important for the potential use of the above compound to act as an anticariogenic agent in oral health applications.

Evaluation of Analyte Transfer between Microfluidic Droplets by Mass Spectrometry.

Droplet microfluidics enables high-throughput experimentation and screening by encapsulating chemical and biochemical samples in aqueous droplets segmented by an immiscible fluid. In such experiments, it is critical that each droplet remains chemically distinct. A common approach is to use fluorinated oils with surfactants to stabilize droplets. However, some small molecules have been observed to transport between droplets under these conditions. Attempts to study and mitigate this effect have relied on evaluating crosstalk using fluorescent molecules, which inherently limits the analyte scope and conclusions drawn about the mechanism of the effect. In this work, transport of low molecular weight compounds between droplets was investigated using electrospray ionization mass spectrometry (ESI-MS) for measurement. The use of ESI-MS significantly expands the scope of analytes that can be tested. We tested 36 structurally diverse analytes that were found to exhibit crosstalk ranging from negligible to complete transfer using HFE 7500 as the carrier fluid and 008-fluorosurfactant as a surfactant. Using this data set, we developed a predictive tool showing that high log P and log D values correlate with high crosstalk, and high polar surface area and log S correlate with low crosstalk. We then investigated several carrier fluids, surfactants, and flow conditions. It was discovered that transport is strongly dependent on all of these factors and that experimental design and surfactant tailoring can reduce carryover. We present evidence for mixed crosstalk mechanisms including both micellar and oil partitioning transfer. By understanding the driving mechanisms, surfactant and oil compositions can be designed to better reduce chemical transport for screening workflows.

A skin pharmacokinetics study of permeation enhancers: The root cause of dynamic enhancement effect on in vivo drug permeation

Skin pharmacokinetics (SPK) of permeation enhancers can answer the question of why enhancement effects different at the kinetic level. Herein, SPK of permeation enhancers were classified into two categories, namely, lateral elimination (elimination to surrounding stratum corneum (SC)) and longitudinal elimination (elimination to deep epidermal (EP)). They were evaluated with a specific parameter for permeation enhancers, diffusion ratio (DRSC-EP), according to results of tissue-distribution test, molecular dynamic (MD) simulation, and confocal laser scanning microscopy (CLSM). The linear relationship between ke-enahcer and Δ Cmax-drug (R2 = 0.92), MRTenhancer and Δ Tmax-drug (R2 = 0.97), AUCt-enhancer and Δ AUCt-drug (R2 = 0.90) suggesting that SPK of permeation enhancers precisely controlled dynamic process of drug permeation in vivo. The molecular mechanisms of the dynamic effect of SPK process on drug transdermal behaviors were characterized by modulated-temperature differential scanning calorimetry (MTDSC), dielectric spectroscopy, small-angle X-ray scattering (SAXS), solid-state NMR. Permeation enhancers with high molecular weight (M.W.) and high polar surface area (P.S.A.) had good compatibility and strong interaction strength with SC, leading their lateral-elimination behavior, causing their low DRSC-EP and resulting in low ke-enhancer, long MRTenhancer, and large AUCt-enhancer. Consequently, skin barrier can be rapidly opened fast and to a great extent. In summary, compared with SPK of permeation enhancers with longitudinal elimination, SPK of permeation enhancers with lateral elimination can enable more sustainable and greater drug permeation. The information about SPK of permeation enhancers offered a criterion to estimate its permeation-enhancement effect on the drug and its subsequent application in transdermal formulations.

HIF1 inhibition of the biflavonoids against pancreas cancer: drug-likeness, bioavailability, ADMET, PASS, molecular docking, molecular dynamics, and MM/GBSA calculations

Pancreatic cancer is an aggressive disease with a high death rate and is difficult to treat. This disease, in the most cases, is asymptomatic until it progresses to an advanced stage. Therefore, the search for bioactive molecules is urgent to combat pancreatic cancer. Then, this work analyzed the interaction potential of agathisflavone and amentoflavone molecules against the HIF1 target using the ADMET, molecular docking, and molecular dynamics simulations. More recent drug-likeness filters that combine physicochemical and physiological parameters have shown that high polar surface area (TPSA > 75 Å2) drives biflavonoids out of the toxic drug space of Pfizer dataset. Regarding the pharmacokinetic descriptors, it was possible to notice that Amentoflavone showed a better order of passive cell permeability (Papp = 8 × 10−6 cm/s) and better metabolic stability, biotransformed by aromatic hydroxylation reactions by the CYP3A4 isoenzyme on the human liver, that favor its hepatic clearance. The molecular docking and molecular dynamics simulations indicated the high interaction potential and stability between the ligands analyzed (highlighted the amentoflavone molecule), respectively. The MM/GBSA calculations showed that the amentoflavone ligand registered the highest ΔG binding value of −32.6957 kcal/mol with the HIF1 target. Then, this molecule may be used as a potential inhibitor of pancreatic cancer. In this perspective, the present work represents an initial step in the virtual bioprospecting a pharmacological tool for treating of pancreatic cancer. Communicated by Ramaswamy H. Sarma

Mesoporous Ti4 O7 Nanosheets with High Polar Surface Area for Catalyzing Separator to Reduce the Shuttle Effect of Soluble Polysulfides in Lithium-sulfur Batteries.

In the effort to accelerate adsorption and catalytic conversion of lithium polysulfides (Li-PSs) and suppress the shuttle effect of lithium-sulfur batteries (LSBs), the Ti4 O7 nanosheets/carbon material-modified separator is successfully fabricated to reducing soluble Li-PSs' crossover from cathode to anode. The catalyst of mesoporous Ti4 O7 nanosheets with O-Ti-O units synthesized at low temperature shows both excellent conductivity and high surface area. The modified separator can serve as a diffusion barrier of Li-PSs and catalyst for converting soluble low-chain sulfides into insoluble ones and then remarkably enhance the sulfur utilization and electrochemical performance of the LSB. This work provides a feasible avenue in both design and synthesis of mesoporous catalyst materials for suppressing the shuttle effect of lithium-sulfur batteries.

Synthesis, Molecular Docking Analysis, and Biological Evaluations of Saccharide-Modified Sulfonamides as Carbonic Anhydrase IX Inhibitors.

Based on the strategy of the “tail approach”, 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds showed good activity against CAs and high topological polar surface area (TPSA) values, which had a positive effect on the selective inhibition of transmembrane isoforms CA IX and XII. In the in vitro activity studies, compounds 16a, 16b, and 16e reduced the viability of HT-29 and MDA-MB-231 cells with a high expression of CA IX under hypoxia. The inhibitory activity of compound 16e on the human osteosarcoma cell line MG-63 with a high expression of CA IX and XII was better than that of AZM. Moreover, high concentrations of compounds 16a and 16b reversed the acidification of the tumour microenvironment. In addition, compound 16a had a certain inhibitory effect on the migration of MDA-MB-231 cells. All the above results indicate that the saccharide-modified sulfonamide has further research value for the development of CA IX inhibitors.

Biochars’ adsorption performance towards moxifloxacin and ofloxacin in aqueous solution: Role of pyrolysis temperature and biomass type

Three different biomass wastes (rice husk, sawdust, and municipal organic waste) were thermally converted to value-added biochars at two pyrolytic temperatures of 300 °C and 700 °C. Resulted biochars were evaluated for their adsorption potential for the two most widely used fluoroquinolone antibiotics, i.e. moxifloxacin and ofloxacin, through sorption experiments. The results showed that biochars pyrolyzed at 300 °C removed a higher percentage of tested antibiotics (up to 96.18%) than those produced at 700 °C (up to 38.74 %). The Langmuir and Freundlich isotherm models fitted well to the sorption data of the antibiotics indicating monolayer to multilayer adsorption onto the biochars. The adsorption kinetics data of both moxifloxacin and ofloxacin was well fitted to the pseudo-second-order model, suggesting that chemisorption could be the dominant mechanism of adsorption of antibiotics onto different biochars. Among all the biochars, the organic waste-derived biochar (synthesized at 300 °C) was the best adsorbent, with an adsorption potential of 39.10 and 57.10 mg g−1 for moxifloxacin and ofloxacin, respectively. Relatively greater adsorption of moxifloxacin than ofloxacin was due to its high polar surface area. The possible cause of chemisorption of antibiotics onto low-temperature (300 °C) biochars was hydrogen bonding and polar interactions. On the whole, the results indicated that biochar produced from organic waste has significant adsorption potential to remove moxifloxacin and ofloxacin from an aqueous solution.

Implications of the Conformationally Flexible, Macrocyclic Structure of the First-Generation, Direct-Acting Anti-Viral Paritaprevir on Its Solid Form Complexity and Chameleonic Behavior.

Direct-acting antiviral regimens have transformed therapeutic management of hepatitis C across all prevalent genotypes. Most of the chemical matter in these regimens comprises molecules well outside the traditional drug development chemical space and presents significant challenges. Herein, the implications of high conformational flexibility and the presence of a 15-membered macrocyclic ring in paritaprevir are studied through a combination of advanced computational and experimental methods with focus on molecular chameleonicity and crystal form complexity. The ability of the molecule to toggle between high and low 3D polar surface area (PSA) conformations is underpinned by intramolecular hydrogen bonding (IMHB) interactions and intramolecular steric effects. Computational studies consequently show a very significant difference of over 75 Å2 in 3D PSA between polar and apolar environments and provide the structural basis for the perplexingly favorable passive permeability of the molecule. Crystal packing and protein binding resulting in strong intermolecular interactions disrupt these intramolecular interactions. Crystalline Form I benefits from strong intermolecular interactions, whereas the weaker intermolecular interactions in Form II are partially compensated by the energetic advantage of an IMHB. Like Form I, no IMHB is observed within the receptor-bound conformation; instead, an intermolecular H-bond contributes to the potency of the molecule. The choice of metastable Form II is derisked through strategies accounting for crystal surface and packing features to manage higher form specific solid-state chemical reactivity and specific processing requirements. Overall, the results show an unambiguous link between structural features and derived properties from crystallization to dissolution, permeation, and docking into the protein pocket.

Discovery of Highly Potent Adenosine A1 Receptor Agonists: Targeting Positron Emission Tomography Probes.

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the in vivo biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A1 receptor (A1R) radiotracer, [11C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study. Since most of the known AR PET radiotracers were antagonists, we propose that an A1R agonist radioligand may possess higher sensitivity to measure changes in endogenous adenosine concentration. Herein, we report our latest findings toward the development of a full agonist adenosine A1 radioligand for PET. Based on a 3,5-dicyanopyridine template, 16 new derivatives were designed and synthesized to optimize both binding affinity and functional activity, resulting in two full agonists (compounds 27 and 29) with single-digit nanomolar affinities and good subtype selectivity (A1/A2A selectivity of ∼1000-fold for compound 27 and 29-fold for compound 29). Rapid O-[11C]methylation provided [11C]27 and [11C]29 in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An in vivo PET study using knockout mice for MDR 1a/a, BCRP, and MRP1 indicated that these compounds might be substrates for brain efflux pumps. In addition, in silico evaluation using multiparameter optimization identified high molecular weight and high polar surface area as the main molecular descriptors responsible for low brain penetration. These results will provide further insight toward development of full agonist adenosine A1 radioligands and also highly potent CNS A1AR drugs.

Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives.

A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.

Enhancement of Electrochemical Redox Reaction By Transition Metal Oxalates for High-Performance Lithium-Sulfur Battery

As the size and usage of electronics are diversified, demand for secondary batteries with higher capacity and performance is increasing. Lithium-sulfur(Li-S) battery is one of the promising next generation battery due to high theoretical capacity(1,672 mAh/g), natural abundance and environmental nontoxic compare to conventional active materials of lithium-ion batteries. However, lithium polysulfide(PS) dissolution issue which causes capacity fade inevitably must be overcome for commercialization.In this study, we introduced first transition metal oxalates as cathode additives which have a high polar surface area to enlarge the electrocatalytic interfacial boundary enabling LiPS redox reactions to occur, by controlling the carbon and metal oxalates ratio. Furthermore, physicochemical interactions between LiPS and metal oxalates were verified by UV-vis, X-ray Photoelectron Spectroscopy and Electrochemical Analysis(Cyclic Voltammetry, Galvanostatic Intermittent Titration Technique, Electrochemical Impedance Spectroscopy). As a result, the modified cathode by the best candidate effectively decreased cell overpotential and improved the cycle stability by maximized electrochemical utilization Figure 1

Enhanced protein degradation by intracellular delivery of pre-fused PROTACs using lipid-like nanoparticles

Proteolysis-targeting chimaera (PROTAC) technology is an emerging approach for achieving targeted degradation of a protein of interest (POI) intracellularly. However, the cell permeability of PROTACs is limited by their high molecular weight and total polar surface area. Moreover, the activation of the proteasome-mediated degradation by PROTAC requires the formation of a ternary (three-component) complex, composed of the PROTAC, the POIs, and E3-ligases related proteins (E3Ps). Simplifying the three-component system to two-component system could theoretically increase the efficiency of the formation of ternary complex and enhance the protein degradation efficiency. Herein, we demonstrate that pre-fusion of PROTACs with E3Ps (called “pre-fused PROTACs”) before administration could transform the original PROTAC system to two-component system. After delivery by lipid nanoparticles, the degradation of POI by pre-fused PROTACs was dramatically increased and accelerated compared with standard PROTACs. Moreover, we demonstrated that this approach could be generalized to another hydrophobic tag (HyT) degrader by demonstrating the improved targeted protein degradation after pre-fusion the HyT degrader with heat shock protein 70 (HSP70).

Using Polar Ion-Pairs to Control Drug Delivery to the Airways of the Lungs.

The rapid absorptive clearance of drugs delivered to the airways of the lungs means that many inhaled medicines have a short duration of action. The aim of this study was to investigate whether forming polar ion-pairs can modify drug absorption to slow down clearance from the airways. Salbutamol was used as a model drug and was formulated as ion-pairs in an aqueous solution with three negatively charged hydrophilic counterions: sulfate (molecular weight (MW) 142), gluconate (MW 218), and phytate (MW 736) (association constants of 1.57, 2.27, and 4.15, respectively) and one negatively charged hydrophobic counterion, octanoate (MW 166) (association constant, 2.56). All of the counterions were well tolerated by Calu-3 human bronchial epithelial cells when screened for toxicity in vitro using conditions that in silico simulations suggested maintain >80% drug-counterion association. The transport of salbutamol ion-pairs with higher polar surface area (PSA), i.e., the sulfate (PSA 52%), gluconate (PSA 50%), and phytate (PSA 79%) ion-pairs, was significantly lower compared to that of the drug alone (PSA 30%, p < 0.05). In contrast, the octanoate ion-pair (PSA 23%) did not significantly alter the salbutamol transport. The transport data for the gluconate ion-pair suggested that the pulmonary absorption half-life of the ion-paired drug would be double that of salbutamol base, and this illustrates the promise of increasing drug polarity using noncovalent complexation as an approach to control drug delivery to the airways of the lungs.

Role of wetting agents and disintegrants in development of danazol nanocrystalline tablets.

Poor wetting and/or particle aggregation are the shortcomings of the dried nanocrystalline suspensions, which subsequently might hinder the superior dissolution performance of the nano-crystalline suspensions. The objective of this study was to evaluate the effect of wetting agents and disintegrants on the dissolution performance of dried nanocrystals of an active pharmaceutical ingredient (API) with poor wetting property. Danazol, a BCS Class II compound with high LogP and low polar surface area, was chosen as a model compound for this study. Danazol nanocrystalline suspension was prepared by wet-media milling and converted into powder via spray granulation either with mannitol or microcrystalline cellulose as carriers at a drug: carrier ratio of 1:9 w/w. Danazol nanocrystalline suspension showed a superior dissolution performance compared to an un-milled danazol suspension. Dried danazol nanocrystals suffered from poor wetting leading to hindered dissolution performance i.e.~40% and~15% drug dissolution within 15min for the mannitol and microcrystalline cellulose-based granules, respectively. Addition of a lipophilic surfactant (i.e. docusate sodium) at a surfactant: drug ratio of 0.015: 1 w/w during granulation helped in retaining the superior drug dissolution rates i.e. more than 80% drug dissolution within 15min for mannitol-based granules by enhancing the wettability of dried danazol nanocrystals when compared to a hydrophilic surfactant (i.e. poloxamer 188) or disintegrant (i.e. sodium starch glycolate or croscarmellose sodium). The fast-dissolving mannitol-based granules containing danazol nanocrystals and docusate sodium were compressed into a tablet dosage form. The tablets containing danazol nanocrystals with docusate sodium showed a superior dissolution performance compared to a tablet containing un-milled danazol with docusate sodium.

The neuroprotective activities of natural products through the Nrf2 upregulation.

Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a basic-region leucine zipper transcription factor that regulates the expression of many Phase II detoxifying/antioxidant enzymes. Many natural products act on the Nrf2 pathway and exhibit their preventive and/or therapeutic effects by activating Nrf2 and subsequently antioxidant enzymes. In this article, we reviewed the research literature that described Nrf2 activation as a mechanism for the neuroprotective effect of natural products. Our results showed that the inhibition of Kelch-like ECH-associated protein 1 and the activation of different intracellular kinases that lead to Nrf2 phosphorylation were the main mechanisms of Nrf2 upregulation suggested for these the natural products. Although some natural compounds such as terpenoids and alkaloids were reported to protect the nervous system by Nrf2 activating, flavonoids and phenolic compounds represent the majority of the reported neuroprotective natural substances that activate Nrf2. We also evaluated the physiochemical properties of some of the same substances to predict their oral bioavailability and central nervous system penetration. The results showed that sulforaphane and berberine have good oral bioavailability and would be predicted to cross through blood-brain barrier (BBB) easily, whereas the flavonoids in general would be predicted to be less effective in BBB transition because of their relatively high polar surface area.

Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016.

Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved). Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance. The University of Washington Drug Interaction Database (DIDB®) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends. Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP>3) and a high total polar surface area (> 75Å2) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively. The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.

Design, synthesis and structure−activity relationship studies of GPR40 agonists containing amide linker

Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus.

Phytochemical residue profiles in rice grains fumigated with essential oils for the control of rice weevil.

In the present study, we investigated the fumigant potential of five edible essential oils (EOs) against Sitophilus oryzae and their phytochemical residues in treated grains. Among the tested EOs, peppermint oil proved significantly effective (P ≤ 0.05) on S.oryzae at 400 μl/L air concentration, inducing 83 and 100% mortalities in with-food and without-food conditions respectively over 72 h exposure. In addition, it was also observed that the binary mixtures of peppermint + lemon oil (1:1 ratio) produced an equivalent effect to that of peppermint oil alone treatments. The phytochemical residue analysis by GC-MS revealed the presence of six compounds upon 72 h exposure to EOs. Further, the analysis of physico-chemical properties of the compounds indicated a positive correlation between polar surface area (PSA) and its residual nature. The residue levels of eugenol were significantly elevated corresponding to its high PSA value (29) in clove and cinnamon oils. On the other hand, the compounds with zero PSA value imparted very less or no (D-Limonene, caryophyllene, pinene and terpinolene) residues in treated grains. With respect to the most active peppermint oil, L-menthone, menthyl acetate and eucalyptol residues were at 67, 41 and 23% levels respectively. The outcome of the present study indicate the peppermint oil as a potent fumigant against S. oryzae, and although the residues of phytochemicals in treated grains is higher; they belong to the generally recognised as safe (GRAS) status leaving no harmful effect.

A STUDY ON EFFECT OF INDOLE AS A SUBSTITUENT ON A KETO-ENOL TAUTOMER: A SYNTHETIC APPROACH ON β-DIKETONE

Objective: The existence of keto-enol tautomerism in β-diketones can typically study by a choice of analytical technique. The position of the keto-enol equilibrium depends on a number of factors like solvent, temperature, and substituents. Here an attempt was made to examine the effect of indole, a heterocyclic moiety with the moderately high polar surface area to examine its effect on ketonisation of β-diketone.Methods: The β-diketone studied and synthesized is a structural analog of magical drug curcumin. The structural influence of indole on ketonisation of β-diketone is studied to give a hypothesis on factors contributing towards ketonisation. This work involves the synthesis of 6-(1H-Indol-3-yl)-hex-5ene-2, 4-dione and the study on the single crystal structure of indole-3-carboxaldehyde, major functional component to result in the reaction. The tautomer was studied for its ability to bind with tetrahydrofolate reductase enzyme using Discovery Studio 3.5 version to differentiate the pharmacological significance of conformations.Results: The single crystal XRD structure of this compound was deposited in Cambridge crystallographic data center bearing CCDC No.1536311. The structural characterization of synthesized ligand was carried out by using IR, Mass, 1H NMR spectroscopic techniques. The docking study reveals that keto isomer found to exhibit more inhibition of the enzyme tetrahydrofolate reductase hence more pharmacologically active.Conclusion: The experimental evidence proves that indole substitution shifted the keto-enol equilibrium towards keto form of 6-(1H-Indol-3-yl)-hex-5ene-2, 4-dione.

Toward Understanding the Cold, Hot, and Neutral Nature of Chinese Medicines Using in Silico Mode-of-Action Analysis.

One important, however, poorly understood, concept of Traditional Chinese Medicine (TCM) is that of hot, cold, and neutral nature of its bioactive principles. To advance the field, in this study, we analyzed compound-nature pairs from TCM on a large scale (>23 000 structures) via chemical space visualizations to understand its physicochemical domain and in silico target prediction to understand differences related to their modes-of-action (MoA) against proteins. We found that overall TCM natures spread into different subclusters with specific molecular patterns, as opposed to forming coherent global groups. Compounds associated with cold nature had a lower clogP and contain more aliphatic rings than the other groups and were found to control detoxification, heat-clearing, heart development processes, and have sedative function, associated with "Mental and behavioural disorders" diseases. While compounds associated with hot nature were on average of lower molecular weight, have more aromatic ring systems than other groups, frequently seemed to control body temperature, have cardio-protection function, improve fertility and sexual function, and represent excitatory or activating effects, associated with "endocrine, nutritional and metabolic diseases" and "diseases of the circulatory system". Compounds associated with neutral nature had a higher polar surface area and contain more cyclohexene moieties than other groups and seem to be related to memory function, suggesting that their nature may be a useful guide for their utility in neural degenerative diseases. We were hence able to elucidate the difference between different nature classes in TCM on the molecular level, and on a large data set, for the first time, thereby helping a better understanding of TCM nature theory and bridging the gap between traditional medicine and our current understanding of the human body.